PROJECT SUMMARY/ ABSTRACT Patients with Alzheimer's disease (AD) frequently experience sleep disruptions. The emergence of sleep fragmentation is an early indicator of memory decline and a risk factor for AD. An increase of ?-amyloid peptides (A?) production and its reduced clearance are associated with sleep disturbances and neuronal excitability. Several AD mouse models of amyloidosis also exhibit sleep abnormalities. Prolonged wakefulness impairs the cAMP-signaling pathway leading to consequences on memory consolidation. While the reciprocal feed-forward regulation of cerebral A? burden and sleep fragmentation are critical issues in AD pathogenesis, the mechanisms underlying these manifestations are not well understood. We propose to explore if intracellular components of the amyloid precursor protein (APP) influence sleep disruptions and the course of AD. The proposed investigations is guided by our findings that elevated APP C-terminal fragments (APP- CTF) facilitate axodendritic outgrowth as a result of intracellular coupling with adenylate cyclase and the activation of CREB signaling. We generated a membrane-tethered APP intracellular domain (mAICD) construct [which is competent for signaling but remains unperturbed by ?-secretase] to achieve constitutive activation of signaling through APP C-terminal tail. Using this tool, we recently demonstrated that sustained APP signaling through a direct interaction of APP cytosolic tail with the heterotrimeric G-protein subunit G?S promotes non-amyloidogenic processing of APP and preserves memory in AD mouse models. Accordingly, we hypothesize that APP-mediated signaling affects sleep conditions in a manner that attenuates or contributes to AD pathology through the regulation of amyloidogenic processing of APP. To test this hypothesis, we propose: (1) to evaluate if APP-mediated signaling tempers memory deterioration associated with sleep disturbances in AD mouse models of amyloidosis and non-amyloidosis; (2) to investigate if APP- mediated signaling affects sleep architecture in AD mice; and (3) to determine if enhanced APP-mediated signaling preserves dynamic regulation of axonal outgrowth and synapses in sleep perturbed AD mice. Using a variety of mouse models, we will address whether the impaired cognition associated with sleep perturbations, necessitate APP expression and ?-secretase-mediated accumulation of APP-CTF. To pursue these objectives, we will express mAICD and a variant that lacks the G?S-protein interaction motif using recombinant adeno-associated virus (rAAV) delivery in the brain of AD mice at early and late stages of the amyloidosis. Mice will be subjected to acute sleep deprivation or chronic sleep fragmentation to examine the significance of APP-mediated signaling and sleep perturbations on cognitive function, A? burden, axodendritic outgrowth and synapse formation. Sleep architecture will be monitored through telemetric recordings. Our complementary approaches will provide more meaningful understanding of how combined genetic mutations and environmental risk factors contribute to accelerating cognitive decline observed in AD.